The most frequently occurring cancer in women, and the second leading cause of cancer death among women, is breast cancer. Cancer results from cellular mutations that enhance proliferation and decrease programmed cell death (apoptosis). Secreted frizzled-related proteins (SFRPs) are a family of proteins known for their ability to negatively modulate the Wnt signalling cascade. SFRP1 expression is lost in a multitude of cancers, including breast cancer, and SFRP1 down regulation reduces apoptosis in vitro but the mechanisms remain unclear, as also the effect of Sfrp1 deficiency on apoptosis on mammary epithelial cells in vivo. Our data show that mammary glands from Sfrp1−/− mice express significantly less Bcl2l11 (Bim) and Bax mRNA in response to DNA damage. The effect of Sfrp1 loss in reducing γ-irradiation induced apoptosis was examined by TUNEL staining and cleaved-caspase-3 immunostaining. The findings show that Sfrp1−/− mice have less DNA fragmentation, whilst caspase-3 expression is decreased, and that p53 expression is generally diminished. Recombinant SFRP1 could replace endogenous expression and elevate the levels of pro-apoptotic and p53-mediated gene expression (Bcl2l, Bax, Cdkn1a and Bbc3) in mammary epithelial cells derived from Sfrp1−/− mice. Thus Sfrp1 plays an important role in mediating mammary epithelial apoptotic response to DNA damage in vivo. The role SFRP1 plays in p53 target gene expression was also noted, which suggests that this pathway may be worth exploiting for novel therapies.